Field of the Invention
The present invention relates to plasma treatment of cancer stem cells.
Brief Description of the Related Art
Plasma is an ionized gas that is generated in high-temperature laboratory conditions. Recent developments in plasma physics research has led to the production of cold plasmas with ion temperature close to room temperature. See, Laroussi M., Kong M., Morfill G. and Stolz W., 2012 Plasma Medicine (Cambridge: Cambridge University Press); Fridman A. and Friedman G., 2013 Plasma Medicine (New York: Wiley); and Keidar, M, and Beilis, I., 2013 Plasma Engineering: Application in Aerospace, Nanotechnology and Bionanotechnology (Oxford: Elsevier). Initial studies demonstrated the non-aggressive nature of the cold plasma whereby plasma can interact with organic materials without causing thermal/electric damage to the cell surface. These developments opened up new avenues for plasma applications in biological settings including wound healing, disinfection and more recently in cancer research. This has led to the development of a new field in biological research known as plasma medicine.
Plasma medicine is a relatively new scientific field emerged from research in application of a low-temperature (or cold) atmospheric plasmas in bioengineering. It became apparent that cold atmospheric plasma (CAP) interaction with tissue allows targeted cell removal without necrosis, i.e. cell disruption. In fact, it was demonstrated that CAP affects cells via a programmable process called apoptosis, a multi-step process leading to cell death. Recent cold plasma therapy studies both in vivo and in vitro exhibited apoptosis in bacterial and mammalian cells including various types of cancer cells. The first in vivo demonstration of CAP anti-cancer potential was performed by Vandamme et al on human U87 glioblastoma xenotransplants. See, Vandamme M., Robert E., Pesnel S., Barbosa E., Dozias S., Sobilo J., Lerondel S., Le Pape A. and Pouvesle J. M., “Antitumor effect of plasma treatment on U87 glioma xenografts: preliminary results,” Plasma Process. Polym. 2010; 7:264. Vandamme M., Robert E., Lerondel S., Sarron V., Ries D., Dozias S., Sobilo J., Gosset D., Kieda C., Legrain B., Pouvesle J. M., Pape A. L., “ROS implication in a new antitumor strategy based on non-thermal plasma,” Int. J. Cancer. 2012; 130:2185-94. This study indicated that treatment over multiple days has been effective in reducing tumor volume and increasing survival time through ROS-mediated apoptosis. In another study the anti-tumor action of CAP was demonstrated on a syngenic mouse melanoma and heterotopic human bladder cancer xenograft models. Keidar M., Walk R., Shashurin A., Srinivasan P., Sandler A., Dasgupta S., Ravi R., Guerrero-Preston R. and Trink B., “Cold plasma selectivity and the possibility of a paradigm shift in cancer therapy,” Br. J. Cancer 2011; 105:1295-301. The ability of CAP to ablate the tumor in a single treatment was one of the most interesting results demonstrated. In particular, tumors of about 5 mm in diameter were ablated after about 2 min of a single treatment.
Nevertheless, it is now widely appreciated that a single tumor is basically comprised of heterogeneous cell populations, each of which displays a diverse cellular morphology, phenotypic expression, tumor initiation capacities and inherent or acquired resistance to anti-cancer drugs. See, Abelson S., Shamai Y., Berger L., Shouval R., Skorecki K., Tzukerman M., “Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer,” Stem cells 2012; 30:415-24 Abelson S., Shamai Y., Berger L., Skorecki K., Tzukerman M., “Niche-dependent gene expression profile of intratumoral heterogeneous ovarian cancer stem cell populations,” PloS one 2013; 8:e83651; Kreso A., O'Brien C. A., van Galen P., Gan O. I., Notta F., Brown A. M., Ng K., Ma J., Wienholds E., Dunant C., Pollen A., Gallinger S., McPherson J., Mullighan C. G., Shibata D., Dick J. E., “Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer,” Science 2013; 339: 543-548; and O'Connor J. P., Rose C. J., Waterton J. C., Carano R. A., Parker G. J., Jackson A., “Imaging intratumor heterogeneity: role in therapy response, resistance, and clinical outcome,” 2015; 21:249-57. The aggressiveness and ingenuity of human cancers emanate mainly from such complex intratumoral heterogeneity, which in turn has been attributed to genetic and epigenetic changes coupled with adaptive responses to the tumor microenvironment. Accumulating evidence demonstrates that the model of ‘cancer stem cells’ (CSC) and the clonal evolution model, mutually contribute to intratumoral heterogeneity, as CSC themselves undergo clonal evolution. See, Marusyk A., Polyak K., “Tumor heterogeneity: causes and consequences,” Biochim Biophys Acta 2010; 1805:105-117; Polyak K., Haviv I., Campbell I. G., “Co-evolution of tumor cells and their microenvironment,” Trends Genet 2009; 25:30-38; Shackleton M., Quintana E., Fearon E. R., Morrison S. J, “Heterogeneity in cancer: cancer stem cells versus clonal evolution,” Cell 2009; 138: 822-829; and Yap T. A., Gerlinger M., Futreal P. A., Pusztai L., Swanton C., “Intratumor heterogeneity: seeing the wood for the trees,” Sci Transl Med 2012; 4:127ps110. The continuous accumulation of mutations generates heterogeneity of cells within a solid tumor and its metastases, and may reflect the process whereby certain subsets of tumor cells become more aggressive in the process of tumor progression.
The limitation of conventional anti-cancer therapies may lead to treatment failure and cancer recurrence mainly due to drug resistance and self-renewal capacities of CSC which are responsible for resistance to standard oncology treatments. Reya T., Morrison S. J., Clarke M. F., Weissman I. L., “Stem cells, cancer, and cancer stem cells,” Nature. 2001; 414:105-111.